Supplementary Material for: Effect of Growth Hormone Therapy on Pubertal Timing: Systematic Review and Meta-analysis

Introduction Recombinant human growth hormone (rhGH) therapy effectively increases height in various disorders of childhood growth. However, whether rhGH affects pubertal timing is unclear. We aimed to review systematically published evidence on the effect of rhGH on pubertal timing. Methods Embase, Medline, and Cochrane library databases were searched until December 2021 on randomized and non-randomized controlled studies of rhGH in children. Results Twenty-five articles (n=1,438 children) were identified describing 12 randomized and 13 non-randomized controlled studies in children with idiopathic short stature (ISS; 15 studies), small for gestational age (n=6 studies), chronic renal failure (n=3), Noonan syndrome (n=1), and growth hormone deficiency (n=1). Significant differences in the effects of rhGH on pubertal timing were found by clinical indication. Only among children with ISS, rhGH promoted earlier age at pubertal timing (mean difference=-0.46 years; 95% CI, -0.90 to -0.03; 9 studies; n total=402) or higher relative risk for pubertal onset during study follow-up (1.26; 95% CI, 1.03 to 1.54; 6 studies; n total=284). Conclusions Treatment with rhGH appears to promote earlier pubertal timing among children with ISS. Evidence was lacking in children with growth hormone deficiency due to the absence of studies with untreated controls.